To develop a physiologically based pharmacokinetic (PBPK) model for apixaban, an oral anticoagulant with a narrow therapeutic index, and to predict PK profiles and potential drug-drug interactions (DDIs) in patients with renal impairment and paediatrics.
A whole-body apixaban PBPK model was developed and validated in SimCYP for healthy adults with or without interacting drugs. The model was extended to renal impairment and paediatrics. Observed PK data in adults were compared with predicted data. The effect of renal function, age and DDIs on apixaban PK was investigated.
The PBPK model successfully predicted the PK of apixaban alone and under the influence of interacting drugs. For patients with renal impairment, the PBPK model successfully predicted the fold change in each impairment group; inhibitory DDI and renal impairment had a synergistic effect on the increase of apixaban exposure (e.g., almost 3-fold increase of AUC in ketoconazole + severe renal impairment group). For infants younger than 1year, the exposure of apixaban decreased with increased weight-normalized clearance. For newborn infants, AUC of apixaban was &gt;2-fold higher than that in children older than 1year. https://www.selleckchem.com/products/SGX-523.html Meanwhile, the effect of DDI seems to be weakened while the effect of renal impairment might be enhanced in infants younger than 1year.
Our study provides a reasonable approach to estimate the dose adjustment for the first use of apixaban in special populations with complex situations, which has the opportunity to make the clinical practice much safer.
Our study provides a reasonable approach to estimate the dose adjustment for the first use of apixaban in special populations with complex situations, which has the opportunity to make the clinical practice much safer.Current consensus on global climate change predicts warming trends with more pronounced temperature changes in winter than summer in the Northern Hemisphere at high latitudes. Moderate increases in soil temperature are generally related to faster rates of soil organic carbon (SOC) decomposition in Northern ecosystems, but there is evidence that SOC stocks have remained remarkably stable or even increased on the Tibetan Plateau under these conditions. This intriguing observation points to altered soil microbial mediation of carbon-cycling feedbacks in this region that might be related to seasonal warming. This study investigated the unexplained SOC stabilization observed on the Tibetan Plateau by quantifying microbial responses to experimental seasonal warming in a typical alpine meadow. Ecosystem respiration was reduced by 17%-38% under winter warming compared with year-round warming or no warming and coincided with decreased abundances of fungi and functional genes that control labile and stable organic carbon decomposition. Compared with year-round warming, winter warming slowed macroaggregate turnover rates by 1.6 times, increased fine intra-aggregate particulate organic matter content by 75%, and increased carbon stabilized in microaggregates within stable macroaggregates by 56%. Larger bacterial "necromass" (amino sugars) concentrations in soil under winter warming coincided with a 12% increase in carboxyl-C. These results indicate the enhanced physical preservation of SOC under winter warming and emphasize the role of soil microorganisms in aggregate life cycles. In summary, the divergent responses of SOC persistence in soils exposed to winter warming compared to year-round warming are explained by the slowing of microbial decomposition but increasing physical protection of microbially derived organic compounds. Consequently, the soil microbial response to winter warming on the Tibetan Plateau may cause negative feedbacks to global climate change and should be considered in Earth system models.Vegetation productivity first increases and then decreases with temperature; and temperature corresponding to the maximum productivity is called optimal temperature (Topt ). In this study, we used satellite derived near-infrared reflectance of vegetation (NIRv ) data to map Topt of vegetation productivity at the spatial resolution of 0.1° on the Tibetan Plateau (TP), one of most sensitive regions in the climate system. The average Topt of non-forest vegetation on the TP is about 14.7°C, significantly lower than the Topt value used in current ecosystem models. A remarkable geographical heterogeneity in Topt is observed over the TP. Higher Topt values generally appear in the north-eastern TP, while the south-western TP has relatively lower Topt ( less then 10°C), in line with the difference of climate conditions and topography across different regions. Spatially, Topt tends to decrease by 0.41°C per 100 m increase in elevation, faster than the elevational elapse rate of growing season temperature, implying a potential CO2 regulation of Topt in addition to temperature acclimation. Topt increases by 0.66°C for each 1°C of rising mean annual temperature as a result of vegetation acclimation to climate change. However, at least at the decadal scale, there is no significant change in Topt between 2000s and 2010s, suggesting that the Topt climate acclimation may not keep up with the warming rate. Finally, future (2091-2100) warming could be close to and even surpass Topt on the TP under different RCP scenarios without considering potential climate acclimation. Our analyses imply that the temperature tipping point when the impact of future warming shifts from positive to negative on the TP is greatly overestimated by current vegetation models. Future research needs to include varying thermal and CO2 acclimation effects on Topt across different time scales in vegetation models.Boreal peatland forests have relatively low species diversity and thus impacts of climate change on one or more dominant species could shift ecosystem function. Despite abundant soil water availability, shallowly rooted vascular plants within peatlands may not be able to meet foliar demand for water under drought or heat events that increase vapor pressure deficits while reducing near surface water availability, although concurrent increases in atmospheric CO2 could buffer resultant hydraulic stress. We assessed plant water relations of co-occurring shrub (primarily Rhododendron groenlandicum and Chamaedaphne calyculata) and tree (Picea mariana and Larix laricina) species prior to, and in response to whole ecosystem warming (0 to +9°C) and elevated CO2 using 12.8-m diameter open-top enclosures installed within an ombrotrophic bog. Water relations (water potential [Ψ], turgor loss point, foliar and root hydraulic conductivity) were assessed prior to treatment initiation, then Ψ and peak sap flow (trees only) assessed after 1 or 2 years of treatments.